Research Findings - International Research

Research Publications by International Program Alumni
Alumni of the NIDA International Program research training and exchange programs authored or coauthored the following articles indexed by PubMed:

Former NIDA INVEST Drug Abuse Research Fellows

Drug Use Opportunities and the Transition to Drug Use among Adolescents from the Mexico City Metropolitan Area
Benjet, C., Borges, G., Medina-Mora, M.E., Blanco, J., Zambrano, J., Orozco, R., Fleiz, C., Rojas, E. Drug Alcohol Depend. 2007 Mar 21; [Epub ahead of print]
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
The earliest stage of drug involvement is being presented with the opportunity to use drugs. During adolescence these opportunities increase. Because of the scarcity of data for the Mexican population, the aim is to estimate the prevalence of drug use opportunities among Mexican adolescents, the prevalence of drug use among those who were presented with the opportunity, and the socio-demographic correlates of both. A multistage probability survey was carried out among 12-17 year olds from Mexico City. Adolescents were administered the adolescent version of the World Mental Health Composite International Diagnostic Interview. The response rate was 71% (n=3005). Descriptive and logistic regression analyses were performed considering the multistage and weighted sample design. Twenty-nine percent have had the opportunity to try illicit drugs; of those presented with an opportunity, 18% have done so. Males, older adolescents, school drop-outs, and those whose parent has had drug problems are more likely to have been exposed to drug use opportunities while more religious adolescents are less likely. Given the chance to try drugs, older adolescents and school drop-outs are more likely to do so and those with high parental monitoring and religiosity are less likely. These results suggest that less substance use among females in Mexico may be due in part to fewer opportunities to use since females were equally likely to use drugs given the opportunity. Given the increase in opportunity among older adolescents, preventive efforts should start by age 12 and with special attention to adolescents who have dropped out of school. PMID: 17382489 [PubMed - as supplied by publisher]

Mental Disorders among English-speaking Mexican Immigrants to the US Compared to a National Sample of Mexicans
Breslau, J., Aguilar-Gaxiola, S., Borges, G., Castilla-Puentes, R.C., Kendler, K.S., Medina-Mora M.E., Su, M., Kessler, R.C.. Psychiatry Res. 2007 Mar 13; [Epub ahead of print].
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
Understanding of the relationship between immigration and mental health can be advanced by comparing immigrants pre- and post-immigration with residents of the immigrants' home countries. DSM-IV anxiety and mood disorders were assessed using identical methods in representative samples of English-speaking Mexican immigrants to the US, a subsample of the US National Comorbidity Survey Replication (NCSR), and Mexicans, the Mexican National Comorbidity Survey (MNCS). Retrospective reports of age of onset of disorders and, in the immigrant sample, age of immigration were analyzed to study the associations of pre-existing mental disorders with immigration and of immigration with the subsequent onset and persistence of mental disorders. Pre-existing anxiety disorders predicted immigration (OR=3.0; 95% CI 1.2-7.4). Immigration predicted subsequent onset of anxiety (OR=1.9; 95% CI 0.9-3.9) and mood (OR=2.3; 95% CI 1.3-4.0) disorders and persistence of anxiety (OR=3.7 95% CI 1.2-11.2) disorders. The results are inconsistent with the "healthy immigrant" hypothesis (that mentally healthy people immigrate) and partly consistent with the "acculturation stress" hypothesis (i.e., that stresses of living in a foreign culture promote mental disorder). Replication and extension of these results in a larger bi-national sample using a single field staff are needed.

Mental Disorders among Adults with Asthma: Results from the World Mental Health Survey
Scott, K.M., Von Korff, M., Ormel, J., Zhang, M.Y., Bruffaerts, R., Alonso, J., Kessler, R.C, Tachimori, H., Karam, E., Levinson, D., Bromet, E.J., Posada-Villa, J., Gasquet, I., Angermeyer, M.C., Borges, G., de Girolamo, G., Herman, A., and Haro, J.M. Gen Hosp Psychiatry. Mar-Apr;29(2), pp.123-133, 2007.
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
Research objectives were (a) to determine which common mental disorders are associated with asthma in the general population after controlling for age and sex, and (b) to assess whether the associations of mental disorders with asthma are consistent across diverse countries. Eighteen population surveys of household-residing adults were carried out in 17 countries (N=85,088). Mental disorders were assessed with the Composite International Diagnostic Interview 3.0, a fully structured diagnostic interview. The disorders considered here are 12-month anxiety disorders (generalized anxiety disorder, panic disorder/agoraphobia, posttraumatic stress disorder and social phobia), depressive disorders (dysthymia and major depressive disorder) and alcohol use disorders (abuse and dependence). Asthma was ascertained by self-reports of lifetime diagnosis among a subsample (n=42,697). Pooled estimates of age-adjusted and sex-adjusted odds of mental disorders among persons with asthma relative to those without asthma were 1.6 [95% confidence interval (95% CI)=1.4, 1.8] for depressive disorders, 1.5 (95% CI=1.4, 1.7) for anxiety disorders and 1.7 (95% CI=1.4, 2.1) for alcohol use disorders. This first cross-national study of the relationship between asthma and mental disorders confirms that a range of common mental disorders occurs with greater frequency among persons with asthma. These results attest to the importance of clinicians in diverse settings being alert to the co-occurrence of these conditions.

The Price of Seizure Control: Dynorphins in Interictal and Postictal Psychosis
Bortolato, M., and Solbrig, M.V. Psychiatry Res. 2007 Mar 27; [Epub ahead of print]
INVEST Fellow: Marco Bortolato, Italy, 2004-2005
Postictal and interictal psychoses are relatively common complicating factors in the clinical course of epilepsy, yet their neurobiological substrates are poorly understood. Recent evidence shows that kappa opioid receptor (KOR) activation elicits anticonvulsant and psychotomimetic effects. In view of this background, here we introduce the hypothesis that epilepsy-related psychoses may partially result from excessive hippocampal dynorphin release and kappa opioid receptor overstimulation aimed at seizure control.

An 18-norspirostanol Saponin with Inhibitory Action against COX-2 Production from the Underground Part of Trillium Tschonoskii
Wang, J., Zou, K., Zhang, Y., Liu, C., Wu, J., Zhou, Y., Dan, F., and Zhang, Y. Chem Pharm Bull (Tokyo). Apr;55(4), pp. 679-681, 2007
INVEST Fellow: Chaung Liu, China, 2000-2001
A novel 18-norspirostanol saponin (1), along with Trillenoside A (2), was obtained from the underground parts of Trillium tschonoskii MAXIM., collected in Shennongjia Forest District, China. Based on the chemical and spectroscopic evidences, their structures were determined as shown in Fig. 1. 1 and 2 displayed marked inhibitory action towards COX-2 production in macrophagocytes of the mouse abdominal cavity stimulated by LPS at 10 microg/ml.

A New Method for Screening and Determination of Diuretics by On-line CE-ESI-MS
Lu, M., Tong, P., Xiao, H., Xia, S., Zheng, X., Liu, W., Zhang, L., and Chen, G. Electrophoresis. 2007 Mar 19; [Epub ahead of print]
INVEST Fellow: Lan Zhang, China, 2004-2005
A rapid, high-resolution and effective new method for analyzing 12 diuretics by CE-ESI-MS was established in this paper. Ten diuretics (except two neutral compounds) could be fast separated by CE with a DAD at 214 nm with a 20 kV voltage within 6 min, using a 50 mum id and 48.5 cm effective length uncoated fused-silica capillary in a 40 mM ammonium formate buffer (pH 9.40). CE was coupled to the mass spectrometer applying an orthogonal electrospray interface with a triple-tube sheath liquid arrangement. The sheath liquid was composed of isopropanol-water (1:1 v/v) containing 30 mM acetic acid with a flow rate of 4 muL/min. Mass spectrum was employed in the positive mode and both full scan mode and SIM scan mode were utilized. All 12 diuretics could be detected and confirmed by MS in a single analysis. Under optimized conditions, LODs for the 12 diuretics were in the range of 0.13-2.7 micromol/L at an S/N of 3, and the correlation coefficients R(2) were between 0.9921 and 0.9978. The RDSs (n = 5) of the method was 0.24-0.94 % for migration times and 1.6-8.8 % for peak areas. The recoveries of spiked samples of 12 diuretics were between 72.4% and 118%. The real urine samples were injected directly for analysis, with only simple filtration through a 0.22 microm membrane filter in order to remove solid particles, which may cause capillary blockage. Based on the migration times and characteristic ions, the diuretics in urine samples were detected successfully. This CE-ESI-MS method for analyzing diuretics will hopefully be applied to doping control.

Risk for Psychiatric Disorder among Immigrants and their US-born Descendants: Evidence from the National Comorbidity Survey Replication
Breslau, J., Aguilar-Gaxiola, S., Borges, G., Kendler, K.S., Su, M., and Kessler, R.C., J Nerv Ment Dis. Mar;195(3), pp. 189-195, 2007.
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
Although previous research has consistently documented that immigrants to the United States have better mental health than US natives, little is known about why this difference occurs. DSM-IV anxiety, mood, impulse control, and substance use disorders were assessed in a nationally representative survey of the US household population, the National Comorbidity Survey Replication. Differences in risk for disorder between immigrants (N = 299) and 5124 natives (N = 5124) were examined using discrete time survival models. Differences were estimated by generation, age of immigration, and duration of residence in the United States. Immigrants had lower lifetime risk of disorder than natives (OR = 0.7; 95% CI, 0.5-0.9). Risk was equally large for natives who were children of immigrants as for natives of subsequent generations. For mood and impulse control disorders, risk equal to that of natives was also found among immigrants who arrived in the United States as children (12 years of age or younger). Immigrants had lower risk than natives prior to arrival in the United States, but there was a trend toward equalization of risk with longer duration of residence in the United States. Differences in risk for disorder emerge within a single generation following immigration, consistent with a strong effect of environmental factors on changes in risk among immigrant populations. This pattern is consistent with either of two causal processes, one involving early socialization in the United States and the other involving postmigration experiences among immigrants who arrive in the United States as adults.

Post-mortem Stability and Redistribution of Carbohydrate-deficient Transferrin (CDT)
Rainio, J., De Paoli, G., Druid, H., Kauppila, R., De Giorgio, F., Bortolotti, F., and Tagliaro, F. Forensic Sci Int. 2007 Apr 30; [Epub ahead of print].
INVEST Fellow: Henrik Druid, Sweden, 2000-2001
Post-mortem diagnosis of chronic alcohol abuse is a challenge for forensic experts due to the lack of pathognomonic morphological findings and often also inadequate background information. Objective methods demonstrating chronic excessive alcohol consumption would therefore be a useful tool for forensic pathologists. In clinical practice, several markers of chronic alcohol abuse have recently been introduced, among which carbohydrate-deficient transferrin (CDT) is the most accepted, but the use of these markers in autopsy has not yet been established. The authors examined post-mortem stability and possible post-mortem redistribution of CDT and compared two analytical methods, capillary zone electrophoresis and high-performance liquid chromatography. According to their results, CDT remains stable for an appreciable time after death. The results further indicate that CDT is not subject to major post-mortem redistribution.

P2X(7)-related Modulation of Pathological Nociception in Rats
McGaraughty, S., Chu, K.L., Namovic, M.T., Donnelly-Roberts, D.L., Harris, R.R., Zhang, XF., Shieh, C.C., Wismer, C.T., Zhu, C.Z., Gauvin, D.M., Fabiyi, A.C., Honore, P., Gregg, R.J., Kort, M.E., Nelson, D.W., Carroll, W.A., Marsh, K., Faltynek, C.R., and Jarvis, M.F.
Neuroscience. 2007 May 1; [Epub ahead of print]
INVEST Fellow: Steven McGaraughty, Canada, 1995-1996
Growing evidence supports a role for the immune system in the induction and maintenance of chronic pain. ATP is a key neurotransmitter in this process. Recent studies demonstrate that the glial ATP receptor, P2X(7), contributes to the modulation of pathological pain. To further delineate the endogenous mechanisms that are involved in P2X(7)-related antinociception, the authors utilized a selective P2X(7) receptor antagonist, A-438079, in a series of in vivo and in vitro experiments. Injection of A-438079 (10-300 mumol/kg, i.p.) was anti-allodynic in three different rat models of neuropathic pain and it attenuated formalin-induced nocifensive behaviors. Using in vivo electrophysiology, A-438079 (80 mumol/kg, i.v.) reduced noxious and innocuous evoked activity of different classes of spinal neurons (low threshold, nociceptive specific, wide dynamic range) in neuropathic rats. The effects of A-438079 on evoked firing were diminished or absent in sham rats. Spontaneous activity of all classes of spinal neurons was also significantly reduced by A-438079 in neuropathic but not sham rats. In vitro, A-438079 (1 muM) blocked agonist-induced (2,3-O-(4-benzoylbenzoyl)-ATP, 30 muM) current in non-neuronal cells taken from the vicinity of the dorsal root ganglia. Furthermore, A-438079 dose-dependently (0.3-3 muM) decreased the quantity of the cytokine, interleukin-1beta, released from peripheral macrophages. Thus, ATP, acting through the P2X(7) receptor, exerts a wide-ranging influence on spinal neuronal activity following a chronic injury. Antagonism of the P2X(7) receptor can in turn modulate central sensitization and produce antinociception in animal models of pathological pain. These effects are likely mediated through immuno-neural interactions that affect the release of endogenous cytokines.

Prophylactic Role for Complementary and Alternative Medicine in Perinatal Programming of Adult Health
Hodgson, D.M., Nakamura, T., and Walker, A.K. Forsch Komplementarmed. Apr;14(2), pp. :92-101, 2007. Epub 2007 Apr 23
INVEST Fellow: Tamo Nakamura, Australia, 2002-2003
The health status of an individual in adulthood is proposed to be determined by events occurring in the prenatal and early postnatal period. A common early life event proven to have long lasting effects on the developing fetus is stress, including pain. Exposure of fetal and neonatal infants to repetitive psychological (e.g., maternal stress) or physiological (e.g., pain, infection, and noise) stress during this period is proposed to alter mechanisms involved in the regulation of stress, immunological maturation, pain perception, and cognition. Such changes, which persist into adulthood, may occur via alterations in the development of the hypothalamic-pituitary-adrenal (HPA) axis. This process is typically referred to as 'perinatal programming'. Ontogenic alterations in the development of the HPA-axis have been related to a number of adult pathologies such as cardiovascular disease, type 2 diabetes, asthma, as well as psychopathologies such as anxiety and depression. In this review, the effectiveness of complementary and alternative medicine (CAM), such as music, dietary supplements, massage and aromatherapy, in reducing perinatal stress in mothers and infants is examined. An emphasis is placed on these therapies as preventative measures which may be of value to individuals at risk of developing disease profiles associated with the consequences of adverse perinatal programming. The widening interest in perinatal programming and CAM suggests the potential for CAM to become a valuable tool in offsetting negative adult health outcomes resulting from perinatal programming associated with adverse gestational early life environments.

Parenting Interventions for Drug-Dependent Mothers and Their Young Children: The Case for an Attachment-Based Approach
Suchman, N., Pajulo, M., Decoste, C., and Mayes, L. Fam Relat. Apr; 55(2), pp. 211-226, 2006.
INVEST Fellow: Marjaterttu Pajulo, Finland, 2003-2004
Maternal substance abuse is the most common factor involved when children come to the attention of the child welfare system. Although there is a clear need for clinical trials to evaluate parenting interventions for drug-dependent women, few studies to date have systematically examined the efficacy of interventions for this population. The authors first review six published reports of outpatient interventions that aimed to enhance the caregiving skills of substance-abusing mothers caring for children between birth and 5 years of age. After discussing implications of these preliminary studies, they then describe an attachment-based intervention that addresses these implications and has demonstrated preliminary feasibility in a pilot trial.

Chinese Herbal Medicine for Schizophrenia: Cochrane Systematic Review of Randomized Trials
Rathbone, J., Zhang, L., Zhang, M., Xia, J., Liu, X., Yang, Y., and Adams, C.E. Br J Psychiatry. May 190, pp.379-384, 2007.
INVEST Fellow: Lan Zhang, China, 2004-2005
Chinese herbal medicine has been used to treat millions of people with schizophrenia for thousands of years. The aim of this study was to evaluate Chinese herbal medicine as a treatment for schizophrenia. A systematic review of randomized controlled trials (RCTs) in which seven trials were included was examined. Most studies evaluated Chinese herbal medicine in combination with Western antipsychotic drugs; in these trials results tended to favor combination treatment compared with antipsychotic alone (Clinical Global Impression ;not improved/worse' n=123, RR=0.19, 95% CI 0.1-0.6, NNT=6,95% CI 5-11; n=109, Brief Psychiatric Rating Scale ;not improved/worse' RR=0.78,95% CI 0.5-1.2; n=109, Scale for the Assessment of Negative Symptoms ;not improved/worse' RR=0.87,95% CI 0.7-1.2; n=109, Scale for the Assessment of Positive Symptoms ;not improved/worse' RR=0.69,95% CI 0.5-1.0, NNT=6 95% CI 4-162). Medium-term study attrition was significantly less for people allocated the herbal/antipsychotic mix (n=897, four RCTs, RR=0.34,95% CI 0.2-0.7, NNT=23,95% CI18-43). Results suggest that combining Chinese herbal medicine with antipsychotics is beneficial.

Drug Dependence in Adolescents 1978-2003: A Clinical-based Observation from North India
Saluja, B.S, Grover, S., Irpati, A.S., Mattoo, S.K., and Basu, D. Indian J Pediatr. May; 74(5), pp. 455-458, 2007.
INVEST Fellow: Debasish Basu, India, 2001-2002
The objective of this work was to study the demographic and clinical profile of adolescent subjects (< or =18 yr) presenting to a state-funded drug de-addiction centre in north India. Data on demographic and clinical features were extracted from available case notes of adolescent patients who presented to the centre during 1978-2003 (n=85). Many adolescents came from nuclear family (63.5%), of urban background (83.5%) and were school dropouts (54.1%). Mean age-at-first-use of the primary substance was 14.8 yr and mean age at first presentation was 17 yr. The most commonly used primary class of substance was opioids (76.2%) and the most commonly used opioid was heroin (36.5%). More than half of the subjects (54.2%) were also nicotine dependent at the time of presentation. The most common reason for starting the use of drugs was curiosity (78.8%). About one-fifth (21.2%) of the subjects indulged in high-risk behavior such as having sexual intercourse with multiple sexual partners. Nearly half of the subjects had positive family history of either drug dependence (40.2%) or psychiatric disorder (5.5%). The results suggest that the development of substance dependence in children and adolescents is a combination of familial and social vulnerability factors, including the drug culture of the social milieu.

Psychiatric Disorders in Mexico: Lifetime Prevalence in a Nationally Representative Sample
Medina-Mora, M.E., Borges, G., Benjet, C., Lara, C., and Berglund, P. Br J Psychiatry. Jun; 190, pp. 521-528, 2007. INVEST Fellow: Guilherme Borges, Mexico, 1997-1998 No national data on lifetime prevalence and risk factors for DSM-IV psychiatric disorders are available in Mexico. The aim of this study was to present data on lifetime prevalence and projected lifetime risk, age at onset and demographic correlates of DSM-IV psychiatric disorders assessed in the Mexican National Comorbidity Survey. The survey was based on a multistage area probability sample of non-institutionalized people aged 18-65 years in urban Mexico. The World Mental Health Survey version of the Composite International Diagnostic Interview was administered by lay interviewers. Of those surveyed, 26.1% had experienced at least one psychiatric disorder in their life and 36.4% of Mexicans will eventually experience one of these disorders. Half of the population who present with a psychiatric disorder do so by the age of 21 and younger cohorts are at greater risk for most disorders. These results suggest an urgent need to re-evaluate the resources allocated for the detection and treatment of psychiatric illnesses in Mexico.

Body Mass Index and the Prevalence of Metabolic Syndrome among Children and Adolescents in Two Mexican Populations
Halley Castillo, E., Borges, G., Talavera, J.O., Orozco, R., Vargas-Alemanm C., Huitron-Bravom G., Diaz-Montiel, J.C., Castanon, S., and Salmeron, J. J Adolesc Health. Jun; 40(6), pp. 521-526, 2007. Epub 2007 Mar 21, 2007. INVEST Fellow: Guilherme Borges, Mexico, 1997-1998 The purpose of this study was to report the prevalence of metabolic syndrome (MS) among children and adolescents living in central Mexico, and its association with body mass index (BMI). In a sample of 1366 subjects from 7 to 24-years-old, a self-administered questionnaire was used to determined demographic characteristics. The definition of pediatric MS was determined using analogous criteria to Adult Treatment Panel III (ATPIII) as > or = 3 of the following: concentration of triglycerides > or = 100 mg/dL, HDL cholesterol < 45 mg/dL for males and < 50 mg/dL for females, waist circumference > or = 75th percentile (sex specific), glucose concentration > or = 110 to < 126 mg/dL, and systolic or diastolic blood pressure > or = 90th percentile (age, height, and sex specific). Most of the sample was in the 10-14- (32.4%) and the 15-19-year (35.4%) age groups, mostly females (57%), and 31% of this young sample was overweight (mean BMI = 21.6 kg/m2). About 1 in every 5 participants had full criteria for MS (19.2%, 95% confidence interval [CI]: 16.4-22.1 among females, and 20.2%, 95% CI: 17.1-23.7 among males), and only 1 in every 10 was free of any MS component. The most common component was a low HDL level, observed in 85.4% of the sample. Unfavorable fat distribution, as indicated by a large waist circumference, was present in 27.9% of the sample. About 66% of those 10-14-year-olds with a large BMI were positive for MS. MS and overweight are major problems for youth in Mexico. Immediate and comprehensive actions at home and schools are needed if Mexico wants to avoid the heavy burden that this disorder will have for its population in the near future.

Smoking and Suicidal Behaviors in the National Comorbidity Survey: Replication
Kessler, R.C., Berglund, P.A., Borges, G., Castilla-Puentes, R.C., Glantz, M.D., Jaeger, S.A., Merikangas, K.R., Nock, M.K., Russo, L.J., and Stang, P.E. J Nerv Ment Dis. May;195(5), pp. 369-377, 2007.
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
Controversy exists about the role of mental disorders in the consistently documented association between smoking and suicidal behavior. This controversy is addressed here with data from the nationally representative National Comorbidity Survey-Replication (NCS-R). Assessments were made of 12-month smoking, suicidal behaviors (ideation, plans, attempts), and DSM-IV disorders (anxiety, mood, impulse-control, and substance use disorders). Statistically significant odds ratios (2.9-3.1) were found between 12-month smoking and 12-month suicidal behaviors. However, the associations of smoking with the outcomes became insignificant with controls for DSM-IV mental disorders. Although clear adjudication among contending hypotheses about causal mechanisms cannot be made from the cross-sectional NCS-R data, the results make it clear that future research on smoking and suicidal behaviors should focus more centrally than previous research on mental disorders either as common causes, markers, or mediators.

Antidepressant-like Activity of the Fatty Acid Amide Hydrolase Inhibitor URB597 in a Rat Model of Chronic Mild Stress
Bortolato, M., Mangieri, R.A., Fu, J., Kim, J.H., Arguello, O., Duranti, A., Tontini, A., Mor, M., Tarzia, G., and Piomelli, D. Biol Psychiatry. 2007 May 16; [Epub ahead of print].
INVEST Fellow: Marco Bortolato, Italy, 2004-2005
The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents. Authors investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression. Daily administration of URB597 (.3 mg.kg(-1), intraperitoneal [IP]) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg.kg(-1), once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg.kg(-1)) or ineffective (.03 mg.kg(-1)). Treatment with URB597 (.3 mg.kg(-1)) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore, the drug regimen increased anandamide levels in midbrain, striatum, and thalamus. URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression. These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain.

Functional Differences in Epigenetic Modulators-Superiority of Mercaptoacetamide-Based Histone Deacetylase Inhibitors Relative to Hydroxamates in Cortical Neuron Neuroprotection Studies
Kozikowski, A.P., Chen, Y., Gaysin, A., Chen, B., D'Annibale, M.A., Suto, C.M., and Langley, B.C. J Med Chem. 2007 Jun 1; [Epub ahead of print].
INVEST Fellow: Yufeng Chen, China, 2003-2004
Authors compare the ability of two structurally different classes of epigenetic modulators, namely, histone deacetylase (HDAC) inhibitors containing either a hydroxamate or a mercaptoacetamide as the zinc binding group, to protect cortical neurons in culture from oxidative stress-induced death. This study reveals that some of the mercaptoacetamide-based HDAC inhibitors are fully protective, whereas the hydroxamates show toxicity at higher concentrations. The present results appear to be consistent with the possibility that the mercaptoacetamide-based HDAC inhibitors interact with a different subset of the HDAC isozymes [less activity at HDAC1 and 2 correlates with less inhibitor toxicity], or alternatively, are interacting selectively with only the cytoplasmic HDACs that are crucial for protection from oxidative stress.

From the Cover: A-803467, A Potent and Selective Nav1.8 Sodium Channel Blocker, Attenuates Neuropathic and Inflammatory Pain in the Rat
Jarvis, M.F., Honore, P., Shieh, C.C., Chapman, M., Joshi, S., Zhang, X.F., Kort, M., Carroll, W., Marron, B., Atkinson, R., Thomas, J., Liu, D., Krambis, M., Liu, Y., McGaraughty, S., Chu, K., Roeloffs, R., Zhong, C., Mikusa, J.P., Hernandez, G., Gauvin, D., Wade, C., Zhu, C., Pai, M., Scanio, M., Shi, L., Drizin, I., Gregg, R., Matulenko, M., Hakeem, A., Gross, M., Johnson, M., Marsh, K., Wagoner, P.K., Sullivan, J.P., Faltynek, C.R., and Krafte, D.S. Proc Natl Acad Sci U S A. May 15;104(20), pp. 8520-8525, 2007.. Epub 2007 May 2.
INVEST Fellow: Steven McGaraughty, Canada, 1995-1996
Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na(v)1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. The authors report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na(v)1.8 (IC(50) = 8 nM) and was >100-fold selective vs. human Na(v)1.2, Na(v)1.3, Na(v)1.5, and Na(v)1.7 (IC(50) values >or=1 microM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na(v)1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.

Relationship Between N-acetyl-aspartate in Gray and White Matter of Abstinent Methamphetamine Abusers and their History of Drug Abuse: A Proton Magnetic Resonance Spectroscopy Study
Sung, Y.H., Cho, S.C., Hwang, J., Kim, S.J., Kim, H., Bae, S., Kim, N., Chang, K.H., Daniels, M., Renshaw, P.F., and Lyoo, I.K. Drug Alcohol Depend. Apr 17;88(1), pp. 28-35, 2007. Epub 2006 Nov 7.
INVEST Fellow: Young Hoon Sung, South Korea, 2005-2006
Altered concentrations of the brain metabolites, including N-acetyl-aspartate (NAA) and myo-inositol (MI), may indicate neurotoxicity associated with drug abuse. In this study, the authors explored differences in brain metabolites between abstinent methamphetamine (MA) abusers and healthy comparison subjects and the associations between metabolite concentrations and clinical characteristics. Proton magnetic resonance spectroscopy (MRS) was performed on 30 abstinent MA abusers and 20 healthy comparison subjects. Two sets of MA user subgroups were defined depending on abstinence duration (greater or less than 6 months) or the total cumulative MA dose (greater or less than 100 g lifetime). NAA and other metabolites were measured in the frontal gray and white matter and compared between MA abuser groups and healthy comparison subjects. MI concentrations were higher for the MA abusers relative to healthy comparison subjects. NAA concentration was lower in frontal white matter of MA abusers with a 'large' cumulative dose relative to those with a 'small' cumulative dose and to healthy comparison subjects. Additionally, in MA abusers NAA concentrations in frontal white matter correlated inversely with the cumulative MA dose. In contrast, there was no significant difference in frontal gray matter NAA concentration among the three groups. However, frontal gray matter NAA concentrations for MA abusers correlated negatively with the total cumulative MA dose and positively with the duration of abstinence. There were no differences between the different MA user groups for MI. The current findings suggest that MA-induced metabolic alterations of frontal gray and white matter are dose-dependent, for primarily male subjects. Additionally, these findings potentially suggest that the MA-related abnormalities may, in part, recover with abstinence in gray matter, but not in the white matter regions.

Effect of Ketamine on Endotoxin-induced Septic Shock in Rats and its Mechanism
Xiao, H., Xu, H.W., Liu, H., and Zhang, L. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. May;19(5), pp. 303-305, 2007. Chinese.
INVEST Fellow: Lan Zhang, China, 2004-2005
The objective of this research was to explore the effect of ketamine on septic shock in rat and its mechanism. Sixty SD rats were randomly divided into control group, model group and ketamine group. Septic shock was replicated by intraperitoneal injection of 20 mg/kg lipopolysaccharide (LPS). The control group was given normal saline only. In the ketamine group, the rats received intraperitoneal injection of 80 mg/kg ketamine 20 minutes before shock and 1 hour (ketamine 40 mg/kg) after shock. The survival time and survival rate were observed in each group. Serum tumor necrosis factor-alpha (TNF-alpha), myocardiac cyclic adenosine monophosphate (cAMP) were determined with radioimmunology assay, and expression of heat shock protein 70 (HSP70) was assessed by immunohistochemistry method. The survival rate was lower in the model group (0) compared with the control group (100%) and the ketamine group (70%), the differences were significant (both P<0.05). TNF-alpha was higher, while cAMP was lower in the model group compared with the control group and the ketamine group (all P<0.01). Positive expression of HSP70 in the model group was lower than the control group, while higher than the ketamine group (both P<0.01). There were no significant differences in TNF-alpha and cAMP between the control group and the ketamine group (both P>0.05). The authors conclude that serum TNF-alpha is increased and myocardiac cAMP is decreased in LPS-induced septic shock, whereas ketamine can inhibit the effect of LPS and protect myocardium against sepsis probably by stimulating the expression of myocardiac HSP70.

Value and Actuality of the Prescription Information for Therapeutic Drug Monitoring of Psychopharmaceuticals: A Comparison with the Medico-Scientific Evidence
Ulrich, S., Hiemke, C., Laux, G., Muller-Oerlinghausen, B., Havemann-Reinecke, U., Riederer, P., Zernig, G., and Baumann, P. Pharmacopsychiatry. May;40(3), pp. 121-127, 2007.
INVEST Fellow: Gerald Zernig, Austria, 1993-1994
Therapeutic drug monitoring (TDM) of psychopharmaceuticals, i.e., the assay of plasma concentrations, is a practical therapeutic application of pharmacokinetic principles in psychiatry. The prescription information (summary of product characteristics, SPC) is provided by pharmaceutical companies according to the requirements of regulatory authorities. The present study investigated the degree of agreement of German SPCs for 48 psychopharmaceuticals with the existing medico-scientific evidence in the area of TDM. For this aim, an empirical summary score of SPC content related to TDM (SPCC (TDM)) was calculated and compared with the level of recommendation of TDM (LOR) of the AGNP-TDM expert group consensus guidelines. Considerable disagreement was found between the information on TDM in SPCs and existing medico-scientific evidence, e.g., in the case of antidepressant and antipsychotic drugs. Even for well studied compounds, such as amitriptyline and clozapine, insufficient information on TDM is included in German SPCs. Small differences existed in the TDM-related information in SPCs of generic drugs with, however, much variance between Germany, Austria and Switzerland. Generally, it must be concluded that deficits exist in the preparation of German SPCs for psychopharmaceutical drugs with respect to empirical pharmacokinetic data, i.e., TDM-relevant information. It is recommended that SPCs of psychopharmaceuticals should be improved in terms of TDM-related information and that target plasma concentrations be adjusted according to the guidelines of the AGNP-TDM expert group. A higher level of good pharmacokinetic practice may be thus achieved.

Phase 1A Safety Assessment of Intravenous Amitriptyline
Fridrich, P., Colvin, H.P., Zizza, A., Wasan, A.D., Lukanich, J., Lirk, P., Saria, A., Zernig, G., Hamp, T., and Gerner, P. J Pain. 2007 May 16; [Epub ahead of print].
INVEST Fellow: Gerald Zernig, Austria, 1993-1994
The antidepressant amitriptyline is used as an adjuvant in the treatment of chronic pain. Among its many actions, amitriptyline blocks Na+ channels and nerves in several animal and human models. As perioperative intravenous lidocaine has been suggested to decrease postoperative pain, amitriptyline, because of its longer half-life time, might be more useful than lidocaine. However, the use of intravenous amitriptyline is not approved by the US Food and Drug Administration. The authors therefore investigated the adverse effects of preoperative intravenous amitriptyline in a typical phase 1A trial. After obtaining written Food and Drug Administration and institutional review board approval, they obtained written consent for preoperative infusion of amitriptyline in an open-label, dose-escalating design (25, 50, and 100 mg, n=5 per group). Plasma levels of amitriptyline/nortriptyline were determined, and adverse effects were recorded in a predetermined symptom list. Infusion of 25 and 50 mg amitriptyline appears to be well tolerated; however, the study was terminated when 1 subject in the 100-mg group developed severe bradycardia. Intravenous infusion of amitriptyline (25 to 50 mg over 1 hour) did not create side effects beyond dry mouth and drowsiness, or dizziness, in 2 of our 10 otherwise healthy participants receiving the 25- to 50-mg dose. An appropriately powered future trial is necessary to determine a potential role of amitriptyline in decreasing postoperative pain. Amitriptyline potently blocks the persistently open Na+ channels, which are known to be instrumental in various pain states. As this occurs at very low plasma concentrations, a single preoperative intravenous infusion of amitriptyline could provide long-lasting pain relief and decrease the incidence of chronic pain.

Socioeconomic Inequality and Mental Health: A Latin American Literature Review
Ortiz-Hernandez, L., Lopez-Moreno, S., and Borges, G. Cad Saude Publica. Jun;23(6), pp. 1255-1272, 2007. Spanish.
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
[Article in Spanish]
This study provides a review of the scientific output in Latin America concerning the impact of socioeconomic status (SES) on mental disorders and drug use or addiction. International and regional databases were analyzed. According to the majority of the studies, adults and adolescents with low SES showed increased risk of mental disorders, and alcohol consumption was higher among individuals with high SES, while low SES was associated with alcohol abuse and addiction, although the evidence was less conclusive. Smoking was more frequent among young people with high SES, but in adults it was more common with low SES. Illicit drug use was more frequent among adults (but not adolescents) with low SES. Prescription drugs tended to be consumed by adults and adolescents with higher SES. Use of solvents was more frequent among low SES adolescents. The studies' observed trends and methodological aspects are also discussed.

Activation of GABA(B) Receptors Reverses Spontaneous Gating Deficits in Juvenile DBA/2J Mice
Bortolato, M., Frau, R., Orru, M., Piras, A.P., Fa, M., Tuveri, A., Puligheddu, M., Gessa, G.L., Castelli, M.P., Mereu, G., and Marrosu, F. Psychopharmacology (Berl). 2007 Jun 29; [Epub ahead of print].
INVEST Fellow: Marco Bortolato, Italy, 2004-2005
Gamma-amino-butyric acid (GABA)(B) receptors play a key role in the pathophysiology of psychotic disorders. The authors previously reported that baclofen, the prototypical GABA(B) agonist, elicits antipsychotic-like effects in the rat paradigm of prepulse inhibition (PPI) of the startle, a highly validated animal model of schizophrenia. Authors studied the role of GABA(B) receptors in the spontaneous PPI deficits displayed by DBA/2J mice. Authors tested the effects of baclofen (1.25-5 mg/kg, intraperitoneal [i.p.]) in DBA/2J and C57BL/6J mice, in comparison to the antipsychotic drugs haloperidol (1 mg/kg, i.p.) and clozapine (5 mg/kg, i.p.). Furthermore, they investigated the expression of GABA(B) receptors in the brain of DBA/2J and C57BL/6J mice by quantitative autoradiography. Baclofen dose-dependently restored PPI deficit in DBA/2J mice, in a fashion similar to the antipsychotic clozapine (5 mg/kg, i.p.). This effect was reversed by pretreatment with the GABA(B) antagonist SCH50211 (50 mg/kg, i.p.). In contrast, baclofen did not affect PPI in C57BL/6J mice. Finally, quantitative autoradiographic analyses assessed a lower GABA(B) receptor expression in DBA/2J mice in comparison to C57BL/6J controls in the prefrontal cortex and hippocampus but not in other brain regions. These data highlight GABA(B) receptors as an important substrate for sensorimotor gating control in DBA/2J mice and encourage further investigations on the role of GABA(B) receptors in sensorimotor gating, as well as in the pathophysiology of psychotic disturbances.

Reference Concentrations of Antidepressants. A Compilation of Postmortem and Therapeutic Levels
Reis, M., Aamo, T., Ahlner, J., and Druid, H. J Anal Toxicol. Jun;31(5), pp. 254-264, 2007.
INVEST Fellow: Henrik Druid, Sweden, 2000-2001
In approximately 95% of all medicolegal autopsies performed in Sweden between 1992 and 2005, femoral blood samples were collected and screened for antidepressant drugs. A total of 8591 cases were identified and used for detailed analysis and interpretation. The present compilation provides information about 15 antidepressant drugs determined in femoral blood from certified fatal intoxications and in postmortem "control cases". The postmortem data were subjected to a previously proposed strategy, based on strictly standardized conditions regarding collection, handling and toxicological analysis of the samples. The postmortem data were compared with a therapeutic drug monitoring material (Group T; n = 16,809). The strict inclusion criteria meant that only 2737 postmortem cases were included in the survey. Accordingly, Group A (n = 330) were certified as deaths involving intoxication with a single antidepressant drug; Group B (n = 864) were deaths involving intoxication with more than one drug and/or with a significant concentration of ethanol; and Group C (n = 1800) were deaths under circumstances not involving incapacitation by drugs. In addition to providing reference levels for each drug, the results may also be used to assess risk of toxicity and supply supplementary information to the standard fatal toxicity index.

Acute Stress Facilitates Hippocampal CA1 Metabotropic Glutamate Receptor-dependent Long-term Depression
Chaouloff, F., Hemar, A., and Manzoni, O. J Neurosci. Jul 4;27(27), pp.7130-7135, 2007.
INVEST Fellow: Olivier Manzoni, France, 1997-1998
Acute stress affects NMDA receptor (NMDAR)-dependent synaptic plasticity in the CA1 region of the hippocampus, with long-term potentiation and long-term depression (LTD) being, respectively, diminished and facilitated by acute exposure to stress. Here, the authors examined whether this facilitatory effect of stress on NMDAR-dependent LTD extends to metabotropic glutamate receptor (mGluR)-dependent LTD at Schaffer collateral-CA1 synapses. Application of a low dose (50 microM) of the selective group 1 mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) promoted LTD in slices from stressed, but not from control, rats. Pretreatment of stressed rats with the glucocorticoid receptor (GR) antagonist RU38486 prevented the facilitation of DHPG-induced LTD (DHPG-LTD), indicating the involvement of corticosterone secretion and, in turn, stimulation of GRs. Finally, pretreatment of slices with an mGluR1, but not an mGluR5, antagonist blunted the sensitizing effect of stress on DHPG-LTD. These results indicate that acute stress, through corticosterone stimulation of GRs, facilitates the expression of mGluR1-dependent DHPG-LTD in the hippocampal CA1 region.

Role of the Cyclic-AMP/PKA Cascade and of P/Q-type Ca(++) Channels in Endocannabinoid-mediated Long-term Depression in the Nucleus Accumbens
Mato, S., Lafourcade, M., Robbe, D., Bakiri, Y., and Manzoni, O.J. Neuropharmacology. 2007 May 5; [Epub ahead of print].
INVEST Fellow: Olivier Manzoni, France, 1997-1998
Glutamate transmission between prefrontal cortex (PFC) and accumbens (NAc) plays a crucial role in the establishment and expression of addictive behaviors. At these synapses exogenous cannabinoid receptor 1 (CB1R) agonists reversibly inhibit excitatory transmission, and the sustained release of endogenous cannabinoids (eCB) following prolonged cortical stimulation leads to long-term depression (LTD). Activation of presynaptic K(+) channels mediates the effects of exocannabinoids, but the transduction pathway underlying the protracted phase of eCB-LTD is unknown. Here we report that the maintenance of eCB-LTD does not involve presynaptic K(+) channels: eCB-LTD was not affected by blockade of K(+) channels with 4-AP (100muM) and BaCl(2) (300muM) (fEPSP=78.9+/-5.4% of baseline 58-60min after tetanus, compared to 78.9+/-5.9% in control slices). In contrast, eCB-LTD was blocked by treatment of the slices with the adenylyl cyclase (AC) activator forskolin (10muM), and with the protein kinase A (PKA) inhibitor KT5720 (1muM) (fEPSP=108.9+/-5.7% in forskolin and 110.5+/-7.7% in KT5720, compared to 80.6+/-3.9% in control conditions). Additionally, selective blockade of P/Q-type Ca(2+) channels with omega-agatoxin-IVA (200nM) occluded the expression of eCB-LTD (fEPSP=113.4+/-15.9% compared to 78.6+/-4.4% in control slices), while blockade of N- with omega-conotoxin-GVIA (1muM) or L-type Ca(2+) channels with nimodipine (1muM), was without effect (fEPSP was 83.7+/-5.3% and 87+/-8.9% respectively). These data show that protracted inhibition of AC/PKA activity and P/Q-type Ca(2+) channels are necessary for expression of eCB-LTD at NAc synapses.

The Reperfusion Injury Model Improvement and the Tolerance Time Investigation of Rabbit Spinal Cord Ichemia Under Normothermia
Yao, J.Y., Weng, H., Zhang, L., Wang, Q.Y., Yuan, Y.Q., Tang, Y., and Li, J.S. Sichuan Da Xue Xue Bao Yi Xue Ban. Jun;38(3), pp. 497-500, 542, 2007. Chinese.
INVEST Fellow: Lan Zhang, China, 2004-2005
[Article in Chinese]
This study is designed to improve the rabbit model of ischemic- reperfusion injury and determine the safe clamping duration relevant to the spinal cord tolerance to ischemia at normothermia. 50 New Zealand white rabbits were assigned randomly to 5 groups (Group C20, C25, C30, C40 and C60, 10 rabbits in each group) according to different clamping durations, ranging from 20 min to 60 min. The rabbits were endotracheally intubated for ventilation, and their left ear arteries were catheterized for monitoring the mean artery pressure. The spinal cord ischemia was induced by infrarenal aorta occlusion. A catheter was inserted into the aorta distal clamped site for monitoring the distal artery pressure. The neurological functional status of animal was assessed with the Tarlov scale system (0 or 1 meaning the rabbit paraplegia), at the moment of revival, 6 h, 24 h, and 48 h after the reperfusion. After last scoring, the lumbar segments of spinal cord (L4-L6) were removed for pathological examination, and the normal motor neurons of anterior horn were counted. Forty-eight hours after the infusion, the severe neurological impairments were not detected in the rabbits whose aorta were only clamped for 20 min (Group C20). However, the rabbits in Group CSO became totally paraplegic, and the rabbits in Group C25 C30 or C40 developed the paraplegia at 30% , 80% or 90% respectively. The median number of normal motor neuron was 12. 5, 10 or 2 respectively in Group C20, C25 or C30, and 0 median number resulted in Group C40 and C60. The rabbit model of ischemic-reperfusion injury is successfully improved, of which the safe clamping duration without spinal cord injury is not more than 20 min at normothermia.

Explaining the Escalation of Drug Use in Substance Dependence: Models and Appropriate Animal Laboratory Tests
Zernig, G., Ahmed, S.H., Cardinal, R.N., Morgan, D., Acquas, E., Foltin, R.W., Vezina, P., Negus, S.S., Crespo, J.A., Stockl, P., Grubinger, P., Madlung, E., Haring, C., Kurz, M., and Saria, A. Pharmacology. Jun 14;80(2-3), pp. 65-119, 2007 [Epub ahead of print].
INVEST Fellow: Gerald Zernig, Austria, 1993-1994
Escalation of drug use, a hallmark of drug dependence, has traditionally been interpreted as reflecting the development of tolerance to the drug's effects. However, on the basis of animal behavioral data, several groups have recently proposed alternative explanations, i.e. that such an escalation of drug use might not be based on (1) tolerance, but rather be indicative of (2) sensitization to the drug's reinforcing effect, (3) reward allostasis, (4) an increase in the incentive salience of drug-associated stimuli, (5) an increase in the reinforcing strength of the drug reinforcer relative to alternative reinforcers, or (6) habit formation. From the pharmacological perspective, models 1-3 allow predictions about the change in the shape of drug dose-effect curves that are based on mathematically defined models governing receptor-ligand interaction and signal transduction. These predictions are tested in the present review, which also describes the other currently championed models for drug use escalation and other components of apparent 'reinforcement' (in its original meaning, like 'tolerance' or 'sensitization', a purely descriptive term). It evaluates the animal experimental approaches employed to support or prove the existence of each of the models and reinforcement components, and recapitulates the clinical evidence, which strongly suggests that escalation of drug use is predominantly based on an increase in the frequency of intoxication events rather than an increase in the dose taken at each intoxication event. Two apparent discrepancies in animal experiments are that (a) sensitization to overall reinforcement has been found more often for psychostimulants than for opioids, and that (b) tolerance to the reinforcing and other effects has been observed more often for opioids than for cocaine. These discrepancies are resolved by the finding that cocaine levels seem to be more tightly regulated at submaximum reinforcing levels than opioid levels are. Consequently, animals self-administering opioids are more likely to expose themselves to higher above-threshold doses than animals self-administering psychostimulants, rendering the development of tolerance to opioids more likely than tolerance to psychostimulants. The review concludes by making suggestions on how to improve the current behavioral experimental approaches. Copyright (c) 2007 S. Karger AG, Basel.

Differential Effects of Intravenous R,S-(+/-)-3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) and its S(+)- and R(-)-enantiomers on Dopamine Transmission and Extracellular Signal Regulated Kinase Phosphorylation (pERK) in the Rat Nucleus Accumbens Shell and Core
Acquas, E., Pisanu, A., Spiga, S., Plumitallo, A., Zernig, G., and Chiara, G.D. J Neurochem. Jul;102(1), pp. 121-132, 2007.
INVEST Fellow: Gerald Zernig, Austria, 1993-1994
R,S(+/-)-3,4-methylenedioxymethamphetamine (R,S(+/-)-MDMA, 'Ecstasy') is known to stimulate dopamine (DA) transmission in the nucleus accumbens (NAc). In order to investigate the post-synaptic correlates of pre-synaptic changes in DA transmission and their relationship with MDMA enantiomers, the authors studied the effects of R,S(+/-)-MDMA, S(+)-MDMA, and R(-)-MDMA on extracellular DA and phosphorylated extracellular signal regulated kinase (pERK) in the NAc shell and core. Male Sprague-Dawley rats, implanted with a catheter in the femoral vein and vertical concentric dialysis probes in the NAc shell and core, were administered i.v. saline, R,S(+/-)-MDMA, S(+)-MDMA, or R(-)-MDMA. Extracellular DA was monitored by in vivo microdialysis with HPLC. Intravenous R,S(+/-)-MDMA (0.64, 1, and 2 mg/kg) increased dialysate DA, preferentially in the shell, in a dose-related manner. S(+)-MDMA exerted similar effects but at lower doses than R,S(+/-)-MDMA, while R(-)-MDMA (1 and 2 mg/kg) failed to affect dialysate DA. R,S(+/-)- and S(+)-MDMA but not R(-)-MDMA increased ERK phosphorylation (expressed as density/neuron and number of pERK-positive neurons/area) in both subdivisions of the NAc. The administration of the D1 receptor antagonist, SCH 39166, prevented the increase in pERK elicited by R,S(+/-)-MDMA and S(+)-MDMA, while the D2/3 receptor antagonist, raclopride, increased pERK in the NAc core per se but failed to affect the R,S(+/-)-MDMA-elicited stimulation of pERK. The present results provide evidence that the DA stimulant effects of racemic MDMA are accounted for by the S(+)-enantiomer and that pERK may represent a post-synaptic correlate of the stimulant effect of R,S(+/-)-MDMA on D1-dependent DA transmission.

Former HHH Drug Abuse Research Fellows

A Comparative Study of HIV/AIDS: The Knowledge, Attitudes, and Risk Behaviors of Schizophrenic and Diabetic Patients in Regard to HIV/AIDS in Nigeria
Ogunsemi, O.O., Lawal, R.A., Okulate, G.T., Alebiosu, C.O., and Olatawura, M.O. MedGenMed. Nov 29;8(4) p. 42, 2006.
HHH Fellow: Rahmaan Lawal, Nigeria, 1997-1998
Studies on knowledge and risk behaviors related to HIV/AIDS reported from developed countries have shown that people with psychiatric disorders constitute a special risk group. In Nigeria, although similar studies have been conducted on various population groups, there has, so far, been no reported study on people suffering from psychiatric disorders. The present study set out to compare knowledge, attitudes, and risk behaviors related to HIV/AIDS among schizophrenic patients and diabetic patients. Ninety-eight consecutive schizophrenic patients attending the outpatient clinics of a psychiatric hospital over a period of 8 weeks completed an interviewer's administered questionnaire. The interview covered demographics, risk behaviors, knowledge related to HIV/AIDS, and patients' attitudes toward people infected with HIV/AIDS. Their responses were compared with those of 56 diabetic patients who were similarly interviewed in a teaching hospital. Results: Compared with the diabetic patients, the schizophrenic patients were significantly less sexually active in the previous 12 months (P < .05). They had more misconceptions about HIV/AIDS and were less tolerant towards people living with HIV/AIDS compared with the diabetic patients. They were also more likely to engage in high-risk behaviors. Mental health providers rarely educate psychiatric patients about HIV/AIDS and should be more involved in doing so. Despite being less sexually active, patients with schizophrenia engaged in risk behaviors as did the diabetic patients.

Brazilian Female Crack Users Show Elevated Serum Aluminum Levels
Pechansky, F., Kessler, F.H., Diemen, L., Bumaguin, D.B., Surratt, H.L., and Inciardi, J.A.
Rev Bras Psiquiatr. Mar;29(1), pp. 39-42, 2007.
HHH Fellow: Flavio Pechansky, Brazil, 1993-1994
There is no information in the literature on the impact of crack smoking using crushed aluminum cans as makeshift pipes, a common form of crack use in Brazil. Since aluminum intake is associated with neurological damage, the authors measured serum aluminum levels in crack smokers. The objective of this study was to ascertain the levels of aluminum in crack users who smoke on makeshift aluminum pipes. 71 female crack smokers, their mean age being 28.0 (+/- 7.7), provided information about their drug use, and had blood samples tested for serum aluminum level. 56 (79%) subjects smoked crack from crushed can pipes, while 15 (21%) smoked from other containers. Fifty-two (73.2%) out of the 71 subjects presented a serum aluminum level of 2 microg/l and 13 (18.3%) had a serum aluminum level of 6 microg/l cut-off point, which is above the reference value. When compared to non-drug users matched by their mean age and gender, they had similar median values and interquartile ranges for serum aluminum level [3 (2-4.6) for crack smokers; 2.9 (1.6-4.1) for controls], but with different means and standard deviations (4.7 +/- 4.9 and 2.9 +/- 1.7, respectively). Crack smokers have high serum aluminum level, but the authors are unsure of its complete association with aluminum cans. Further studies are needed. If such association is proven true in future research, further issues will be raised in dealing with this important disorder, including proper planning and evaluation of public health policies in this area.

Drug Consumption Among Sexual Offenders Against Females
Baltieri, D.A., and de Andrade, A.G. Int J Offender Ther Comp Criminol. 2007 Jul 5; [Epub ahead of print].
HHH Fellow: Arthur Guerra de Andrade, Brazil, 1991-1992
This article aims to evaluate the role of drug consumption among sexual offenders against females. Three groups of participants (N =133) comprising sexual offenders against girls, pubertal females, and women were examined with reference to history of drug and/or alcohol use, impulsivity level, sexual addiction, and recidivism risk. Sexual offenders against women were found to have significantly more difficulties with drug use, higher impulsivity level, and to be younger than the sexual offenders against girls and pubertal females. The combination of drug consumption and higher level of impulsivity may contribute to sexual aggression against adult females.

Alcohol and Drug Consumption Among Sexual Offenders
Baltieri, D.A., and de Andrade, A.G. Forensic Sci Int. 2007 Jun 12; [Epub ahead of print]
HHH Fellow: Arthur Guerra de Andrade, Brazil, 1991-1992
The purpose of this study was to evaluate the role of alcohol and drug consumption between sexual offenders against boys and girls. It was an observational, retrospective and cross-sectional study carried out by the Ambulatory for the treatment of sexual disorders of ABC Medical College, Santo Andre, Sao Paulo, Brazil (ABSex). The sample comprised 104 convicts, over 18 years old, sentenced only for sexual crimes against children (below 11 years old). Alcohol and drug consumption, sexual abuse history, sexual impulsivity, and risk of recidivism were evaluated. The sexual offenders against boys showed higher alcohol consumption problems than sexual offenders against girls (chi(2)=19.76, 1d.f., p<0.01). The severity of alcohol consumption was also significantly higher in the sexual offenders against non-related boys than in the sexual offenders against non-related girls (p=0.037, ANOVA). After adjustment for other variables, such as monthly income before the penalty and alcohol consumption at the moment of the crime, the alcohol consumption severity in sexual offenders against boys was significantly higher than in sexual offenders against girls (OR=1.05, CI 1.01-1.08, p<0.01). Alcohol use or abuse is associated with the perpetration of sexual aggression. The role of alcohol consumption seems to be greater in sexual offenders against boys than in girls and this can contribute to criminal recidivism.

Is Attention-Deficit/Hyperactivity Disorder Associated with Illicit Substance Use Disorders in Male Adolescents? A Community-Based Case-Control Study
Szobot, C.M., Rohde, L.A., Bukstein, O., Molina, B.S., Martins, C., Ruaro, P., and Pechansky, F.
Addiction. Jul;102(7), pp. 1122-1130, 2007.
HHH Fellow: Flavio Pechansky, Brazil, 1993-1994
This study aims at evaluating the association between attention-deficit/hyperactivity disorder (ADHD) and illicit substance use disorders (SUD) (marijuana, cocaine and inhalants), controlling for the association with conduct disorder (CD), in a community-based sample of adolescents. Case-control, community-based study. The study was conducted in a delimited geographical area in the South of Brazil, served by four public health clinics. A total of 968 male adolescents (15-20 years of age) were screened for SUD in their households. Of the subjects who were screened positive, the authors selected 61 cases with illicit SUD. For each case selected, from the group which was screened negative, three controls without illicit or alcohol SUD, matched by age and proximity with the case's household. The screening instrument was the Alcohol Smoking and Substance Screening Test (ASSIST). SUD diagnoses were assessed by the drug section of the Mini International Neuropsychiatry Interview (MINI). Other psychiatric diagnoses were based on semistructured (Schedule for Affective Disorders and Schizophrenia for School-Age Children-epidemiological version; MINI) and clinical interviews. Adolescents with ADHD presented a significantly higher odds ratio (OR) for illicit SUD than youths without ADHD, even after adjusting for potential confounders (CD, ethnicity, religion and estimated IQ) (OR = 9.12; 95% CI = 2.84-29.31, P < 0.01). These results suggest an association between ADHD and illicit SUD in Brazilian adolescents that is not mediated by CD. These findings are potentially important from a prevention perspective because treatments are available for ADHD.